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Introduction Fistulizing Crohn’s disease (CD) represents a severe and disabling phenotype characterised by transmural inflammation, defective epithelial repair, and chronic tissue remodelling. Despite its major clinical impact, the molecular features that distinguish fistulizing from non-fistulizing CD remain poorly defined. We aimed to identify proteomic and metabolomic alterations associated with fistula formation in CD using a large population-based cohort.Methods We identified 2,889 individuals with Crohn’s disease, including 217 with fistulizing disease, from the UK Biobank. Baseline demographic, plasma proteomic, and metabolomic data were analysed. Differential expression was assessed using limma with adjustment for age and sex. Pathway and network analyses were performed to support biological interpretation and multiomic integration.Results Fistulizing CD exhibited a distinct proteomic profile enriched for inflammatory, innate immune, and tissue-remodelling pathways. Neutrophil-associated and inflammasome-related mediators, including MPO, MMP9, LCN2, CASP8, and ZBP1, were significantly elevated, consistent with heightened neutrophil activation, epithelial injury, and pro-inflammatory cell death signalling. Proteins involved in cytoskeletal dynamics and extracellular matrix remodelling (ARHGAP5, EFNB2, STX3, STX7) were also increased, indicating active transmural tissue reorganization. In contrast, epithelial integrity and repair–associated proteins (KRT18, ROBO1, GALNT10, MAN1A2) were reduced, suggesting impaired mucosal regeneration.Metabolomic profiling further differentiated fistulizing CD, with reductions in HDL-related lipid fractions and selected amino acid metabolites, alongside increases in VLDL lipids, branched-chain amino acids, acetate, and citrate, reflecting a pro-inflammatory, energy-demanding metabolic state. Integrated multiomic analysis revealed strong internal coherence, with neutrophil-derived proteins clustering with markers of oxidative stress and NAD-dependent metabolic activation (NAMPT, NMNAT1), while lipid and amino acid alterations aligned with pathways regulating immune activation and extracellular matrix turnover. Several dysregulated molecules mapped to pathways directly implicated in fistula biology, including MMP9-mediated matrix degradation, NAMPT-driven NAD+ inflammatory metabolism, and branched-chain amino acid–dependent mTOR signalling.Conclusions Multiomic profiling identifies a robust molecular signature distinguishing fistulizing from non-fistulizing Crohn’s disease. These findings implicate coordinated neutrophil activation, epithelial repair failure, extracellular matrix remodelling, and metabolic reprogramming as central components of fistula biology, providing mechanistic insights and highlighting candidate biomarkers and therapeutic targets for this aggressive disease phenotype.